High-purity ferromagnetic iron oxide pigments

ABSTRACT

γ-Fe 2  O 3  pigments and Fe 3  O 4  pigments with a particle diameter of 2 to 100 nm, a saturation magnetization above 40 nTm 3  /g, a remanence below 10 nTm 3  /g, a Cr content below 40 mg/kg of pigment, a Cu content below 40 mg/kg of pigment and C content below 100 mg/kg of pigment and aqueous suspension of these pigments. The pigments are used in aqueous suspension in the medical sector, in particular as contrast agents in magnetic resonance imaging.

The present invention relates to high-purity γ-Fe₂ O₃ pigments and Fe₃O₄ pigments with a particle diameter of 2-100 nm, a saturationmagnetization above 40 nTm³ /g, a remanence below 10 nTm³ /g, a Crcontent below 40 mg/kg of pigment, a Cu content below 40 mg/kg ofpigment and a C content below 100 mg/kg of pigment.

The invention additionally relates to processes for preparing thesepigments, to aqueous suspensions which contain these pigments, and tothe use of the pigments and suspensions in the medical sector.

Ferromagnetic iron oxide pigments are known to be usable in the medicalsector in particular in the form of an aqueous suspension, as contrastagents in magnetic resonance imaging.

The pigments are known to be prepared by reacting an aqueous solution ofiron salts with a base, adjusting the iron valency required in thepigment by using iron(II) and iron(III) salts or, if the iron valency istoo low, by oxidative treatment of the solution, eg. with atmosphericoxygen. The precipitate is then separated off and washed and dried in aconventional way.

The iron salts used as starting compounds still contain, however, smallamounts of salts of other metals such as chromium, nickel and copper.These impurities do not interfere with use for most purposes but are notphysiologically acceptable if, like contrast agents, they are putdirectly into the bloodstream in the human body.

Furthermore, iron pigments suitable for magnetic resonance imaging mustmeet high demands in respect of ferromagnetic sensitivity, for which thelevel of the saturation magnetization at low remanence represents ameasure, in order thereby to keep the dose of the agent as small aspossible. Finally, these contrast agents should have particles as fineas possible so that they will dissolve faster in the blood and do notform any deposits which are difficult to break down on the blood vesselwalls.

Contrast agents with these properties have not previously beenavailable, and accordingly it is an object of the present invention toremedy this deficiency.

It is an object of the present invention therefore to prepare, in anindustrially simple and economic manner, ferromagnetic iron oxidepigments which are suitable for medical purposes, in particular ascontrast agents for magnetic resonance imaging, and which have adistinctly reduced content of impurities.

We have found that this object is achieved by γ-Fe₂ O₃ pigments and Fe₃O₄ pigments with an average particle diameter of 2-100 nm, a saturationmagnetization above 40 nTm³ /g, a remanence below 10 nTm³ /g, a Crcontent below 40 mg/kg of pigment, a Cu content below 40 mg/kg ofpigment and a C content below 100 mg/kg of pigment.

We have additionally found a process for preparing these pigments, andthe use of these pigments as contrast agents in magnetic resonanceimaging.

It is necessary to employ the iron or an iron oxide in highly pure formas precursor for preparing pigments of this type. Precursors of thistype can be obtained from iron compounds obtainable by simple chemicalor physical purification, preferably distillation. Particularly suitablefor this purpose are volatile iron compounds, in particular ironcarbonyls such as iron pentacarbonyl.

Iron pentacarbonyl can be prepared and purified by distillation in aconventional way, as described, for example, in Ullmann's Encyclopediaof Industrial Chemistry, 5th edition, volume A14, pages 595-601 , VCHVerlagsgesellschaft mbH, 1989.

Iron can be obtained in a conventional way from iron pentacarbonyl bythermal decomposition at 60°-300° C., preferably 150°-250° C. Suitablefor preparing iron oxides from iron carbonyls are normally oxidativedecomposition of iron pentacarbonyl with oxygen or an oxygen-containinggas.

Iron oxides of these types, some of which are commercially available,have a considerable content of non-ferromagnetic iron oxides such asα-Fe₂ O₃ with a large particle size which is unwanted for use ascontrast agents in magnetic resonance imaging, and must thereforeconverted into fine-particle, ferromagnetic iron oxides such as γ-Fe₂ O₃or Fe₃ O₄.

γ-Fe₂ O₃ particles of this type can be prepared by dissolving the ironor, advantageously, an iron oxide, in particular an oxide of trivalentiron, in a high-purity aqueous mineral acid, preferably hydrochloricacid. When iron is used, or when the iron oxide is not in trivalent formor is only partially in trivalent form, oxidizing conditions arepreferably used, in particular in the presence of oxygen or anoxygen-containing gas. The ferromagnetic pigment is then precipitated byadding the solution gradually to a mineral base, preferably sodiumhydroxide solution. To obtain particles of the desired fineness, theprecipitation is carried out with vigorous stirring, the energypreferably being 0.05-5 kWh per kg of the precipitation mixture. It isadvisable to carry out the precipitation at from 5° to 40° C.,preferably 10° to 30° C.

After the precipitation, the precipitate is separated off bydecantation, filtration or centrifugation and washed until ions are nolonger detectable in the eluate. The pigment can then be dried orconverted directly into an aqueous suspension ready for use.

To prepare Fe₃ O₄ it is suitable to dissolve iron or an iron oxide in ahigh-purity aqueous mineral acid, preferably hydrochloric acid. Themolar ratio of trivalent to divalent iron should be adjusted to 2:1 orapproximately 2:1 if the iron oxide used does not (approximately) havethis ratio. If the average valency of the iron is too low, this can takeplace by oxidation, preferably with oxygen or an oxygen-containing gas,and if the average valency of the iron is too high it can take place byreduction or, advantageously, by adding an iron(II) salt solutionobtainable, for example, by dissolving pure iron in a high-purityaqueous mineral acid under non-oxidizing conditions, such as under aprotective gas. Further reaction with a mineral base shouldadvantageously be carried out as described above.

The pigments according to the invention are primarily used for preparingaqueous suspensions which in turn are particularly used as contrastagents for magnetic resonance imaging. The pigment concentration in thesuspensions is preferably 0.0001 to 0.6, in particular 0.001 to 0.3, %by weight. As medical products, these suspensions can containauxiliaries in conventional amounts, eg. physiologically acceptableprotective colloids or dispersants such as polyacrylates or proteins,and buffer substances to adjust a pH which is preferably from 6 to 12,in particular from 6.5 to 8. Otherwise, the suspensions are used formagnetic resonance imaging in the same way as conventional products ofthis type.

EXAMPLE

7.8 kg of high-purity 38% by weight hydrochloric acid were added to asuspension of 2 kg of high-purity α-Fe₂ O₃ in 10 kg of distilled water,and the mixture was heated until the iron oxide had dissolved.

After this solution had cooled to room temperature it was mixed with 4.7kg of a 33% by weight iron(II) chloride solution which had been preparedby dissolving extra pure iron in high-purity hydrochloric acid.

The resulting solution was then gradually added under nitrogen withvigorous stirring (0.9 kWh stirring energy) to 17.5 kg of a 25% byweight NaOH solution at 20° C. over the course of 13.5 h.

The precipitate was filtered off, washed and dried.

It contained as impurities 24 mg of chromium, <30 mg of copper and 80 mgof carbon per kg of pigment and had an average particle diameter of 15nm. The saturation magnetization was 74 nTm³ /g and the remanence was 5nTm³ /g.

We Claim:
 1. A process for preparing ferromagnetic iron oxide pigmentshaving an average particle diameter of 2-100 nm, a saturationmagnetization above 40 nTm³ /g, a remanence below 10 nTm³ /g, whichcomprises dissolving iron or an iron oxide which contains below 40 ppmCr, below 40 ppm Cu and below 100 ppm C in a high-purity aqueous mineralacid, and precipitating γ-Fe₂ O₃ from this solution at 5°-40° C. withvigorous stirring using a mineral base, operating under oxidizingconditions in the case of iron or if the iron oxide employed is notpresent in trivalent form or is only partially present in trivalentform, and washing and drying the fine-particle precipitate obtained inthis way.
 2. The process of claim 1, wherein γ-Fe₂ O₃ pigments areprepared.
 3. A process for preparing ferromagnetic iron oxide pigmentspas claimed in claim 1, having a saturation magnetization above 40 nTm³/g and a remanence below 10 nTm³ /g, which comprises dissolving iron oran iron oxide which contains below 40 ppm Cr, below 40 ppm Cu and below100 ppm C in a high-purity aqueous mineral acid, adjusting a molar ratioof trivalent to divalent iron of 2:1 or approximately 2:1 if thesolution does not have this ratio or approximately this ratio, andprecipitating Fe₃ O₄ from this solution at 5°-40° C. with vigorousstirring using a mineral base, and washing and drying the fine-particleprecipitate obtained in this way.
 4. The process of claim 3, wherein Fe₃O₄ pigments are prepared.